This proposal describes a 5 year training program which builds on Dr. Briasouli's doctoral and postdoctoral experiences in cell signaling/oncology to transition toward her development of an independent, extramurally-funded, translational program focusing on autoimmune mediated tissue injury in general and congenital heart block (CHB) in particular. In accord with this goal, a career plan has been formulated by Dr. Briasouli in cooperation with her primary sponsor, Dr. Jill Buyon. The translational expertise of Dr. Buyon in the study of CHB, her experience as P.I. of a National Registry of affected patients and families, and longstanding record of mentorship, will be complemented by two basic scientists: Dr. Robert Clancy who has worked extensively on the pathogenesis of CHB and Dr. Audrey Bernstein, an expert in the basic biology of the uPA/uPAR system under study. Further acquisition of scientific skills related to the research plan will be provided by Dr. Daniel Rifkin, an expert in TGFbeta, Dr. Thomas Neubert, an expert in mass spectrometry, and Dr. Tom Gordon, an expert in Ro60 and apoptosis. Formal coursework in immunology and structural biology will be integral to the training program and enhanced by attendance in immunology and rheumatology weekly seminars and journal clubs. Improvement of communication skills will be fostered by presentations in diverse settings;research in progress, journal clubs, grand rounds, and abstract submissions to national meetings. Institutional commitment is strong with anticipation of immediate promotion to Instructor and rapid advancement to Assistant Professor. Dr. Briasouli's proposal builds on her novel finding that uPAR may be critical in the cascade to CHB by virtue of its increased expression/function following anti-Ro60 binding to apoptotic cells, which results in two pathogenic events fueling an amplification loop to inflammation/fibrosis. One is a "don't eat me" signal to healthy cardiocytes attempting clearance of remodeling cells and the other is the generation of plasmin. Aim 1 explores the mechanisms by which anti-Ro60 exploits uPAR to inhibit apoptotic clearance. In Aim 2, Dr. Briasouli investigates the consequences of the anti-Ro60-dependent increase of plasminogen activation in triggering inflammation/fibrosis focusing on activation of latent TGF21 and macrophage migration. In Aim 3, proof of concept is addressed by evaluation of uPAR levels and expression in cord blood samples and autopsies of CHB-hearts, respectively. The health significance of this proposal is supported by the absence of prevention and treatment of this lifelong disease of passively acquired autoimmunity. PUBLIC HEALTH RELEVANCE: All women with anti-Ro antibodies face the alarming prospect of having a child with a lifelong cardiac disease. To date there is no prevention or cure of this disease. This training program will foster the development of a promising basic scientist who has already made a novel discovery regarding the mechanism by which anti-Ro antibodies may cause tissue injury in the heart.